Use of antagonists of aldosterone in patients with chronic kidney disease: potential advantages and risks

The question of whether or not to use aldosterone antagonists in subjects with proteinuria and chronic kidney disease (CKD) is assuming increasing clinical relevance. The role of the renin–angiotensin–aldosterone system (RAAS) in the progression of CKD is undisputed [1,2] as is the notion that inhibition of the RAAS with angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin type 1 receptor antagonists (ARBs) may retard but not abrogate CKD progression [3–6]. More recently, studies suggest that antagonists of aldosterone may also mitigate proteinuria and progression of CKD. Although aldosterone is partly controlled by angiotensin II expression, many patients exhibit ‘aldosterone escape’ in which aldosterone levels remain high despite inhibition of the RAAS with ACEIs or ARBs [7]. In addition, many diabetic patients continue to have proteinuria despite recommended doses of ACEIs and ARBs. Because proteinuria is an independent risk factor for progressive renal disease, investigators are searching for additional pathogenic mechanisms and alternative therapeutic tools, such as aldosterone blockade, to arrest or abrogate proteinuria and CKD progression. Aldosterone may lead to progression of CKD and proteinuria through a variety of mechanisms. Studies in experimental rat models have shown that aldosterone participates in the progression of kidney disease through hemodynamic and direct cellular actions [8–10]. ACEIs and ARBs do not suppress aldosterone predictably, leaving potentially detrimental effects of aldosterone unabated [11], and antagonists of aldosterone retard the progression or cause regression of existing glomerulosclerosis independently of effects on blood pressure (BP) [12]. In rats with subtotal nephrectomy and adrenalectomy, proteinuria, hypertension and structural renal injury were less pronounced than in rats with intact adrenal glands [13]. Aldosterone infusion abrogated the beneficial effects of ACEIs in stroke-prone spontaneously hypertensive rats (SHRSP), whereas spironolactone reduced vascular injury and proteinuria in these animals [14,15]. The clinical evidence supporting a role of aldosterone in CKD progression is scanty but involves both diabetic and non-diabetic patients with CKD [7,16–18]. In an uncontrolled trial of eight patients with various renal diseases and proteinuria >1 g/day, spironolactone consistently reduced proteinuria by 53% [19]. In a short-term (8-week) uncontrolled study, Bianchi et al. [20] observed that 25 mg/day of spironolactone effectively reduced proteinuria by approximately 37% in 42 non-diabetic CKD patients already treated with ACEI and/or ARBs. In this study [20], baseline levels of aldosterone were significantly correlated with the degree of reduction in proteinuria following treatment with spironolactone. In 13 patients with early diabetic nephropathy and ‘aldosterone escape’ from ACEIs, Sato et al. [7] observed a significant reduction in urinary albumin excretion after 24 weeks of treatment with spironolactone. Of note, the decrease in urine albumin excretion was more pronounced among patients with aldosterone escape. Rachmani et al. [18] compared the antiproteinuric effects of spironolactone with those of cilazapril in 60 women with diabetic nephropathy. Spironolactone reduced proteinuria more effectively than ACEIs, and the combined administration of ACEIs and spironolactone was more effective than either drug alone. Similar findings were observed by Epstein et al. [21]. These investigators showed that eplerenone reduced proteinuria more effectively than an ACE inhibitor in patients with type 2 diabetes mellitus. A combination of eplerenone and ACE inhibitor was more effective than either drug given alone in reducing proteinuria. In 41 patients with CKD, Chrysostomou et al. [22] showed a significant reduction in proteinuria with spironolactone, which persisted 6–12 months after initiation of therapy. Spironolactone treatment in addition to recommended antihypertensive drugs reduced BP and proteinuria in type 1 and type 2 diabetic patients with nephropathy [23,24]. In this issue of the Journal of Hypertension, van den Meiracker et al. [25] report the first placebo-controlled, double-blind trial in type 2 diabetic patients with diabetic nephropathy already treated with an ACEI or ARB; 29 of these patients were allocated to spironolactone (25–50 mg/day) and 30 to placebo for a period of 1 year. Albuminuria decreased by more than 40% in patients treated with spironolactone, but it did not change in patients treated with placebo. The investigators also observed a rapid decrease in estimated glomerular filtration rate (eGFR) in spironolactone-treated patients which leveled off over time. Conversely, in the placebo group, the investigators observed a progressive, linear decline in eGFR. One patient in the placebo group and five patients in the spironolactone group developed hyperkalemia despite reduction in the dose of spironolactone to 25 mg, and had to be excluded. Hyperkalemic patients tended to have a higher baseline creatinine level and lower eGFR. Other investigators have also reported an initial reduction in eGFR after initiation of treatment with spironolactone [20]. The mechanisms responsible for the initial reduction in eGFR are unclear. However, this phenomenon is reminiscent of the initial fall in eGFR seen in CKD patients treated with ACEIs, whereby an initial rapid decrease in GFR is usually followed by stabilization of kidney function. Whereas the pattern of rapid reduction followed by stabilized eGFR translates into improved long-term renal survival with ACE inhibition, this remains to be proven with aldosterone receptor blockade. In fact, the eGFR was significantly lower in the spironolactone group than the placebo group at the end of 1 year in the study by van den Meiracker et al. [25], and directly correlated with the reduction in proteinuria. Larger, long-term studies are needed to demonstrate whether or not the stabilization of renal function with aldosterone receptor blockers is persistent over time and leads to benefits in renal outcome. The mechanisms responsible for the adverse renal effects of aldosterone are complex and likely multifactorial. Schmidt et al. [26] have shown that aldosterone exerts rapid nongenomic effects on the renal vasculature, resulting in increased renal vascular resistance in the context of endothelial nitric oxide synthase (eNOS) inhibition. Chun and Pratt [27] have suggested that under conditions of endothelial dysfunction, as might occur in patients with essential hypertension, metabolic syndrome or CKD, these nongenomic effects of aldosterone may result in reduced renal blood flow and GFR. Arima et al. [28] observed that aldosterone causes vasoconstriction of both the afferent and efferent arterioles from rabbit kidneys, but more on the efferent than the afferent arterioles. Endothelial denudation and pharmacological blockade of eNOS increased the sensitivity of the afferent arterioles to aldosterone, suggesting that nitric oxide modulates the vasoconstrictor action of aldosterone [29]. Eplerenone decreased GFR in a dog model of obesity-induced hypertension [30]. In all, these studies suggest that antagonists of aldosterone may reduce GFR due to direct effects on the renal microcirculation. In addition to adverse alterations in intrarenal hemodynamics, aldosterone may also exert deleterious effects on the kidney by inflammation and direct damage. Aldosterone increases type IV collagen accumulation in rat mesangial cells [31] and stimulates plasminogen activator inhibitor-1 (PAI-1), which is centrally involved in the pathogenesis of fibrinolysis, and both of these effects may contribute to glomerulosclerosis and tubulo-interstitial nephritis [32,33]. Aldosterone stimulates transforming growth factor-β1 (TGF-β1), a cytokine that promotes fibroblast differentiation and proliferation [34], and aldosterone antagonists improve cyclosporine-induced nephrotoxicity [35]. Eplerenone inhibits lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1)-mediated adhesion molecules, resulting in improved endothelial function [36]. Nagase et al. [37] observed that a high salt diet caused proteinuria and glomerulosclerosis in 4-week-old Dahl salt-sensitive rats. The increase in proteinuria was associated with a decrease in nephrin and an increase in markers of podocyte damage, such as B7-1 and desmin. Pretreatment with eplerenone dramatically reduced podocyte damage as well as proteinuria and glomerulosclerosis. In conclusion, aldosterone may play an important causative role in proteinuria and progression of kidney disease, and antagonists of aldosterone may reduce proteinuria and, hopefully, the rate of progression of CKD. Larger prospective randomized trials of longer duration are needed to demonstrate conclusively the beneficial effects of aldosterone antagonists on the progression of CKD. Concerns remain with regard to the risk of hyperkalemia, particularly in patients with more advanced kidney disease treated with ACEIs and ARBs. Future studies are also needed to determine the ideal time to initiate aldosterone antagonists as adjunctive therapy to other inhibitors of the renin–angiotensin system, especially given the risk of hyperkalemia. Antagonists of aldosterone may be considered a useful additional tool in the management of patients with proteinuria resistant to other interventions, but not enough studies exist to advocate their use as a primary agent in preventing progression of CKD at this time.